Efficacy of Lorlatinib in Treatment-Naive Patients With ALK-Positive Advanced NSCLC in Relation to EML4::ALK Variant Type and ALK With or Without TP53 Mutations

Introduction: Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, improved outcomes compared with crizotinib in patients with previously untreated ALK-positive advanced NSCLC in the phase 3 CROWN study. Here, we investigated response correlates using plasma circulating tumor DNA (ctDNA) an...

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Autores: Bearz, A., Martini, J.-F., Jassem, J., Kim, S.-W., Chang, G.-C., Shaw, A.T., Shepard, D.A., Dall'O, E., Polli, A., Thurm, H., Zalcman, G., García Campelo, María del Rosario, Penkov, K., Hayashi, H., Solomon, B.J.
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Servizo Galego de Saúde (SERGAS)
Repositorio:RUNA. Repositorio da Consellería de Sanidade e Sergas
OAI Identifier:oai:runa.sergas.gal:20.500.11940/21427
Acceso en línea:https://portalcientifico.sergas.gal//documentos/6522c809ec1a10197ffd9822
http://hdl.handle.net/20.500.11940/21427
Access Level:acceso abierto
Palabra clave:Humans
Crizotinib
Lung Neoplasms
Antineoplastic Agents
Anaplastic Lymphoma Kinase
Carcinoma, Non-Small-Cell Lung
Lactams, Macrocyclic
Protein Kinase Inhibitors
Mutation
Tumor Suppressor Protein p53
AS A Coruña
CHUAC
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oai_identifier_str oai:runa.sergas.gal:20.500.11940/21427
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network_name_str España
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spelling Efficacy of Lorlatinib in Treatment-Naive Patients With ALK-Positive Advanced NSCLC in Relation to EML4::ALK Variant Type and ALK With or Without TP53 MutationsBearz, A.Martini, J.-F.Jassem, J.Kim, S.-W.Chang, G.-C.Shaw, A.T.Shepard, D.A.Dall'O, E.Polli, A.Thurm, H.Zalcman, G.García Campelo, María del RosarioPenkov, K.Hayashi, H.Solomon, B.J.HumansCrizotinibLung NeoplasmsAntineoplastic AgentsAnaplastic Lymphoma KinaseCarcinoma, Non-Small-Cell LungLactams, MacrocyclicProtein Kinase InhibitorsMutationTumor Suppressor Protein p53AS A CoruñaCHUACIntroduction: Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, improved outcomes compared with crizotinib in patients with previously untreated ALK-positive advanced NSCLC in the phase 3 CROWN study. Here, we investigated response correlates using plasma circulating tumor DNA (ctDNA) and tumor tissue profiling. Methods: ALK fusions and ALK with or without TP53 mutations were assessed by next-generation sequencing. End points included objective response rate (ORR), duration of response, and progression-free survival (PFS) by blinded independent central review on the basis of EML4::ALK variants and ALK with or without TP53 or other mutation status. Results: ALK fusions were detected in the ctDNA of 62 patients in the lorlatinib arm and 64 patients in the crizotinib arm. ORRs were numerically higher with lorlatinib versus crizotinib for EML4::ALK variant 1 (v1; 80.0% versus 50.0%) and variant 2 (v2; 85.7% versus 50.0%) but were similar between the arms for variant 3 (v3; 72.2% versus 73.9%). Median PFS in the lorlatinib arm was not reached for EML4::ALK v1 and v2 and was 33.3 months for v3; in the crizotinib arm, median PFS was 7.4 months, not reached, and 5.5 months, respectively. ORRs and PFS were improved with lorlatinib versus crizotinib regardless of TP53 mutation status and in patients harboring preexisting bypass pathway resistance alterations. In the lorlatinib arm, PFS was lower in patients who had a co-occurring TP53 mutation. Results from ctDNA analysis were similar to those observed with tumor tissue samples. Conclusions: Patients with untreated ALK-positive advanced NSCLC derived greater clinical benefits, with higher ORRs and potentially longer PFS, when treated with lorlatinib compared with crizotinib, independent of EML4::ALK variant or ALK mutations, TP53 mutations, or bypass resistance alterations.The authors thank the participating patients and their families, investigators, subinvestigators, research nurses,study coordinators, and operations staff. Editorial and medical writing support was provided by Meredith Rogers, MS, CMPP, and Marius Dettmer, PhD, of CMC AFFINITY, McCann Health Medical Communications, and Eleanor Porteous, MSc, of Clinical Thinking, Inc., and was funded by Pfizer. This study was sponsored by Pfizer.2023info:eu-repo/semantics/articlehttps://portalcientifico.sergas.gal//documentos/6522c809ec1a10197ffd9822http://hdl.handle.net/20.500.11940/21427reponame:RUNA. Repositorio da Consellería de Sanidade e Sergasinstname:Servizo Galego de Saúde (SERGAS)Ingléshttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:runa.sergas.gal:20.500.11940/214272026-06-12T08:40:47Z
dc.title.none.fl_str_mv Efficacy of Lorlatinib in Treatment-Naive Patients With ALK-Positive Advanced NSCLC in Relation to EML4::ALK Variant Type and ALK With or Without TP53 Mutations
title Efficacy of Lorlatinib in Treatment-Naive Patients With ALK-Positive Advanced NSCLC in Relation to EML4::ALK Variant Type and ALK With or Without TP53 Mutations
spellingShingle Efficacy of Lorlatinib in Treatment-Naive Patients With ALK-Positive Advanced NSCLC in Relation to EML4::ALK Variant Type and ALK With or Without TP53 Mutations
Bearz, A.
Humans
Crizotinib
Lung Neoplasms
Antineoplastic Agents
Anaplastic Lymphoma Kinase
Carcinoma, Non-Small-Cell Lung
Lactams, Macrocyclic
Protein Kinase Inhibitors
Mutation
Tumor Suppressor Protein p53
AS A Coruña
CHUAC
title_short Efficacy of Lorlatinib in Treatment-Naive Patients With ALK-Positive Advanced NSCLC in Relation to EML4::ALK Variant Type and ALK With or Without TP53 Mutations
title_full Efficacy of Lorlatinib in Treatment-Naive Patients With ALK-Positive Advanced NSCLC in Relation to EML4::ALK Variant Type and ALK With or Without TP53 Mutations
title_fullStr Efficacy of Lorlatinib in Treatment-Naive Patients With ALK-Positive Advanced NSCLC in Relation to EML4::ALK Variant Type and ALK With or Without TP53 Mutations
title_full_unstemmed Efficacy of Lorlatinib in Treatment-Naive Patients With ALK-Positive Advanced NSCLC in Relation to EML4::ALK Variant Type and ALK With or Without TP53 Mutations
title_sort Efficacy of Lorlatinib in Treatment-Naive Patients With ALK-Positive Advanced NSCLC in Relation to EML4::ALK Variant Type and ALK With or Without TP53 Mutations
dc.creator.none.fl_str_mv Bearz, A.
Martini, J.-F.
Jassem, J.
Kim, S.-W.
Chang, G.-C.
Shaw, A.T.
Shepard, D.A.
Dall'O, E.
Polli, A.
Thurm, H.
Zalcman, G.
García Campelo, María del Rosario
Penkov, K.
Hayashi, H.
Solomon, B.J.
author Bearz, A.
author_facet Bearz, A.
Martini, J.-F.
Jassem, J.
Kim, S.-W.
Chang, G.-C.
Shaw, A.T.
Shepard, D.A.
Dall'O, E.
Polli, A.
Thurm, H.
Zalcman, G.
García Campelo, María del Rosario
Penkov, K.
Hayashi, H.
Solomon, B.J.
author_role author
author2 Martini, J.-F.
Jassem, J.
Kim, S.-W.
Chang, G.-C.
Shaw, A.T.
Shepard, D.A.
Dall'O, E.
Polli, A.
Thurm, H.
Zalcman, G.
García Campelo, María del Rosario
Penkov, K.
Hayashi, H.
Solomon, B.J.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Humans
Crizotinib
Lung Neoplasms
Antineoplastic Agents
Anaplastic Lymphoma Kinase
Carcinoma, Non-Small-Cell Lung
Lactams, Macrocyclic
Protein Kinase Inhibitors
Mutation
Tumor Suppressor Protein p53
AS A Coruña
CHUAC
topic Humans
Crizotinib
Lung Neoplasms
Antineoplastic Agents
Anaplastic Lymphoma Kinase
Carcinoma, Non-Small-Cell Lung
Lactams, Macrocyclic
Protein Kinase Inhibitors
Mutation
Tumor Suppressor Protein p53
AS A Coruña
CHUAC
description Introduction: Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, improved outcomes compared with crizotinib in patients with previously untreated ALK-positive advanced NSCLC in the phase 3 CROWN study. Here, we investigated response correlates using plasma circulating tumor DNA (ctDNA) and tumor tissue profiling. Methods: ALK fusions and ALK with or without TP53 mutations were assessed by next-generation sequencing. End points included objective response rate (ORR), duration of response, and progression-free survival (PFS) by blinded independent central review on the basis of EML4::ALK variants and ALK with or without TP53 or other mutation status. Results: ALK fusions were detected in the ctDNA of 62 patients in the lorlatinib arm and 64 patients in the crizotinib arm. ORRs were numerically higher with lorlatinib versus crizotinib for EML4::ALK variant 1 (v1; 80.0% versus 50.0%) and variant 2 (v2; 85.7% versus 50.0%) but were similar between the arms for variant 3 (v3; 72.2% versus 73.9%). Median PFS in the lorlatinib arm was not reached for EML4::ALK v1 and v2 and was 33.3 months for v3; in the crizotinib arm, median PFS was 7.4 months, not reached, and 5.5 months, respectively. ORRs and PFS were improved with lorlatinib versus crizotinib regardless of TP53 mutation status and in patients harboring preexisting bypass pathway resistance alterations. In the lorlatinib arm, PFS was lower in patients who had a co-occurring TP53 mutation. Results from ctDNA analysis were similar to those observed with tumor tissue samples. Conclusions: Patients with untreated ALK-positive advanced NSCLC derived greater clinical benefits, with higher ORRs and potentially longer PFS, when treated with lorlatinib compared with crizotinib, independent of EML4::ALK variant or ALK mutations, TP53 mutations, or bypass resistance alterations.
publishDate 2023
dc.date.none.fl_str_mv 2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://portalcientifico.sergas.gal//documentos/6522c809ec1a10197ffd9822
http://hdl.handle.net/20.500.11940/21427
url https://portalcientifico.sergas.gal//documentos/6522c809ec1a10197ffd9822
http://hdl.handle.net/20.500.11940/21427
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:RUNA. Repositorio da Consellería de Sanidade e Sergas
instname:Servizo Galego de Saúde (SERGAS)
instname_str Servizo Galego de Saúde (SERGAS)
reponame_str RUNA. Repositorio da Consellería de Sanidade e Sergas
collection RUNA. Repositorio da Consellería de Sanidade e Sergas
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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